| Summary: | Background: Infertility affects one in six couples (1) and hence is an important health issue, which can have significant medical, psychological and financial implications for couples. In vitro fertilization (IVF) is an effective treatment for infertility. However, one of the major complications that can arise from IVF treatment is ovarian hyperstimulation syndrome (OHSS). OHSS is predominantly related to the mode of triggering oocyte maturation during IVF treatment. It has been previously reported that a single dose of kisspeptin results in an LH-surge of ~12-14hrs duration, which safely triggers oocyte maturation in women at high risk of OHSS, but has yet to be directly compared with other triggers. I hypothesised that increasing the duration of LH-exposure by administering a second dose of kisspeptin could further optimise oocyte maturation without increasing the incidence of OHSS. Ovarian volume and ascitic fluid are commonly used to categorise the severity of OHSS in diagnostic guidelines. I also aimed to address if ovarian volume at early OHSS screening (day 2-10 following oocyte retrieval) altered when using different triggers of oocyte maturation (hCG, GnRH agonist or kisspeptin). Methods: This was a phase-2 single-blinded randomised placebo-controlled trial of 62 women at high risk of OHSS undergoing IVF treatment at Hammersmith Hospital, 5 London, UK. Following a recombinant FSH/GnRH-antagonist superovulation protocol, all patients (n=62) received a subcutaneous injection of kisspeptin-54 (9.6nmol/kg) 36hrs prior to oocyte retrieval. Patients were then randomised 1:1 to receive either a second dose of kisspeptin (D; Double, n=31), or saline (S; Single, n=31) 10hrs thereafter. Oocytes were retrieved transvaginally 36h after kisspeptin injection, assessed for maturation (primary outcome), and fertilised by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. A second retrospective study was conducted assessing all women at high risk of OHSS (antral follicle count ≥23), aged < 35yrs, BMI < 30 kg/m2 with both ovaries intact, for sonographic signs and for OHSS symptoms during early OHSS screening (2-10 days following oocyte retrieval) at Hammersmith Hospital, London, UK (2013-2016). Ovarian volume on ultrasound, ascitic volume and OHSS symptoms were determined when patients were triggered with (hCG) (n=44), GnRH agonist (GnRHa) (n=94) or kisspeptin (n=115) at time of early OHSS screening. Results A second injection of kisspeptin significantly induced further LH-secretion at 4hrs and 10hrs after injection compared to saline (P < 0.0001). A higher proportion of patients achieved satisfactory oocyte yield following a second dose of kisspeptin (S:45.2%, D:71.0%; absolute difference +25.8%, CI 2.1-49.5%, P=0.042). There was no difference in the frequency of OHSS between the two groups. The mean 6 implantation rates following a double dose were higher (37.1±48.2%) when compared to a single dose (23.3±43%) of kisspeptin. Average mean ovarian volume (MOV) following hCG trigger was 172mls ±89mls, 88 ±60mls after GnRHa trigger and 53±37mls following kisspeptin trigger (p < 0.0001). The mean change in ovarian volume from baseline to OHSS screening for hCG was 166±87mls (25-fold), 75±56mls (10-fold) with GnRHa and 41±35mls (6-fold) following kisspeptin (p < 0.0001). OHSS symptoms were reported most frequently following hCG and least with kisspeptin. Conclusion Administering a second dose of kisspeptin safely improves oocyte yield in women undergoing IVF treatment. Kisspeptin may thus present a safer alternative than GnRHa or hCG triggering in patient at high risk of OHSS.
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